1seu
From Proteopedia
(New page: 200px<br /> <applet load="1seu" size="450" color="white" frame="true" align="right" spinBox="true" caption="1seu, resolution 3.00Å" /> '''Human DNA Topoisome...) |
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| - | [[Image:1seu.gif|left|200px]]<br /> | + | [[Image:1seu.gif|left|200px]]<br /><applet load="1seu" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1seu" size=" | + | |
caption="1seu, resolution 3.00Å" /> | caption="1seu, resolution 3.00Å" /> | ||
'''Human DNA Topoisomerase I (70 Kda) In Complex With The Indolocarbazole SA315F and Covalent Complex With A 22 Base Pair DNA Duplex'''<br /> | '''Human DNA Topoisomerase I (70 Kda) In Complex With The Indolocarbazole SA315F and Covalent Complex With A 22 Base Pair DNA Duplex'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Human topoisomerase I (top1) is the molecular target of a diverse set of | + | Human topoisomerase I (top1) is the molecular target of a diverse set of anticancer compounds, including the camptothecins, indolocarbazoles, and indenoisoquinolines. These compounds bind to a transient top1-DNA covalent complex and inhibit the resealing of a single-strand nick that the enzyme creates to relieve superhelical tension in duplex DNA. (Hertzberg, R. P.; et al. Biochem. 1989, 28, 4629-4638. Hsiang, Y. H.; et al. J. Biol. Chem 1985, 260, 14873-14878. Champoux, J. J. Annu. Rev. Biochem. 2001, 70, 369-413. Stewart, L.; et al. Science 1998, 729, 1534-1541.) We report the X-ray crystal structures of the human top1-DNA complex bound with camptothecin and representative members of the indenoisoquinoline and indolocarbazole classes of top1 poisons. The planar nature of all three structurally diverse classes allows them to intercalate between DNA base pairs at the site of single-strand cleavage. All three classes of compounds have a free electron pair near Arg364, a residue that if mutated confers resistance to all three classes of drugs. The common intercalative binding mode is augmented by unexpected chemotype-specific contacts with amino acid residues Asn352 and Glu356, which adopt alternative side-chain conformations to accommodate the bound compounds. These new X-ray structures explain how very different molecules can stabilize top1-DNA covalent complexes and will aid the rational design of completely novel structural classes of anticancer drugs. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1SEU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SA3 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/DNA_topoisomerase DNA topoisomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.99.1.2 5.99.1.2] Full crystallographic information is available from [http:// | + | 1SEU is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SA3:'>SA3</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/DNA_topoisomerase DNA topoisomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.99.1.2 5.99.1.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1SEU OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Burgin, A | + | [[Category: Burgin, A B.]] |
[[Category: Cushman, M.]] | [[Category: Cushman, M.]] | ||
| - | [[Category: Feese, M | + | [[Category: Feese, M D.]] |
[[Category: Pommier, Y.]] | [[Category: Pommier, Y.]] | ||
| - | [[Category: Staker, B | + | [[Category: Staker, B L.]] |
[[Category: Stewart, L.]] | [[Category: Stewart, L.]] | ||
[[Category: Zembower, D.]] | [[Category: Zembower, D.]] | ||
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[[Category: topoisomerase i]] | [[Category: topoisomerase i]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:00:44 2008'' |
Revision as of 13:00, 21 February 2008
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Human DNA Topoisomerase I (70 Kda) In Complex With The Indolocarbazole SA315F and Covalent Complex With A 22 Base Pair DNA Duplex
Contents |
Overview
Human topoisomerase I (top1) is the molecular target of a diverse set of anticancer compounds, including the camptothecins, indolocarbazoles, and indenoisoquinolines. These compounds bind to a transient top1-DNA covalent complex and inhibit the resealing of a single-strand nick that the enzyme creates to relieve superhelical tension in duplex DNA. (Hertzberg, R. P.; et al. Biochem. 1989, 28, 4629-4638. Hsiang, Y. H.; et al. J. Biol. Chem 1985, 260, 14873-14878. Champoux, J. J. Annu. Rev. Biochem. 2001, 70, 369-413. Stewart, L.; et al. Science 1998, 729, 1534-1541.) We report the X-ray crystal structures of the human top1-DNA complex bound with camptothecin and representative members of the indenoisoquinoline and indolocarbazole classes of top1 poisons. The planar nature of all three structurally diverse classes allows them to intercalate between DNA base pairs at the site of single-strand cleavage. All three classes of compounds have a free electron pair near Arg364, a residue that if mutated confers resistance to all three classes of drugs. The common intercalative binding mode is augmented by unexpected chemotype-specific contacts with amino acid residues Asn352 and Glu356, which adopt alternative side-chain conformations to accommodate the bound compounds. These new X-ray structures explain how very different molecules can stabilize top1-DNA covalent complexes and will aid the rational design of completely novel structural classes of anticancer drugs.
Disease
Known disease associated with this structure: DNA topoisomerase I, camptothecin-resistant OMIM:[126420]
About this Structure
1SEU is a Single protein structure of sequence from Homo sapiens with as ligand. Active as DNA topoisomerase, with EC number 5.99.1.2 Full crystallographic information is available from OCA.
Reference
Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex., Staker BL, Feese MD, Cushman M, Pommier Y, Zembower D, Stewart L, Burgin AB, J Med Chem. 2005 Apr 7;48(7):2336-45. PMID:15801827
Page seeded by OCA on Thu Feb 21 15:00:44 2008
Categories: DNA topoisomerase | Homo sapiens | Single protein | Burgin, A B. | Cushman, M. | Feese, M D. | Pommier, Y. | Staker, B L. | Stewart, L. | Zembower, D. | SA3 | Complex (isomerase/dna) | Dna | Drug | Poison | Topoisomerase i
